Fetuin-A acts as both an inhibitor of calcification and insulin signaling. Previous studies reported conflicting results on the association between fetuin-A and cardiometabolic diseases. We aim to provide further insights into the association between genetically predicted levels of fetuin-A and cardiometabolic diseases using a Mendelian randomization strategy. Genetic variants associated with fetuin-A and their effect sizes were obtained from previous genetic studies. A series of two-sample Mendelian randomization analyses in 412,444 unrelated individuals from the UK Biobank did not show evidence for an association of genetically predicted fetuin-A with any stroke, ischemic stroke, or myocardial infarction. We do find that increased levels of genetically predicted fetuin-A are associated with increased risk of type 2 diabetes (OR = 1.21, 95%CI 1.13–1.30, P = < 0.01). Furthermore, genetically predicted fetuin-A increases the risk of coronary artery disease in individuals with type 2 diabetes, but we did not find evidence for an association between genetically predicted fetuin-A and coronary artery disease in those without type 2 diabetes (P for interaction = 0.03). One SD increase in genetically predicted fetuin-A decreases risk of myocardial infarction in women, but we do not find evidence for an association between genetically predicted fetuin-A and myocardial infarction in men (P for interaction = < 0.01). Genetically predicted fetuin-A is associated with type 2 diabetes. Furthermore, type 2 diabetes status modifies the association of genetically predicted fetuin-A with coronary artery disease, indicating that fetuin-A increases risk in individuals with type 2 diabetes. Finally, higher genetically predicted fetuin-A reduces the risk of myocardial infarction in women, but we do not find evidence for an association between genetically predicted fetuin-A and myocardial infarction in men.

BACKGROUND: Vascular calcification is associated with increased mortality in patients with cardiovascular disease. Secondary calciprotein particles are believed to play a causal role in the pathophysiology of vascular calcification. The maturation time (T ₅₀ ) of calciprotein particles provides a measure of serum calcification propensity. We compared T ₅₀ between patients with ST-segment–elevated myocardial infarction and control subjects and studied the association of T ₅₀ with cardiovascular risk factors and outcome. METHODS: T ₅₀ was measured by nephelometry in 347 patients from the GIPS-III trial (Metabolic Modulation With Metformin to Reduce Heart Failure After Acute Myocardial Infarction: Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction: a Randomized Controlled Trial) and in 254 matched general population controls from PREVEND (Prevention of Renal and Vascular End-Stage Disease). We also assessed the association between T ₅₀ and left ventricular ejection fraction, as well as infarct size, the incidence of ischemia-driven reintervention during 5 years of follow-up, and serum nitrite as a marker of endothelial dysfunction. RESULTS: Patients with ST-segment–elevated myocardial infarction had a significantly lower T ₅₀ (ie, higher serum calcification propensity) compared with controls (T ₅₀ : 289±63 versus 338±56 minutes; P <0.001). In patients with ST-segment–elevated myocardial infarction, lower T ₅₀ was associated with female sex, lower systolic blood pressure, lower total cholesterol, lower LDL (low-density lipoprotein) cholesterol, lower triglycerides, and higher HDL (high-density lipoprotein) cholesterol but not with circulating nitrite or nitrate. Ischemia-driven reintervention was associated with higher LDL ( P =0.03) and had a significant interaction term for T ₅₀ and sex ( P =0.005), indicating a correlation between ischemia-driven reintervention and T ₅₀ above the median in men and below the median in women, between 150 days and 5 years of follow-up. CONCLUSIONS: Serum calcification propensity is increased in patients with ST-segment–elevated myocardial infarction compared with the general population, and its contribution is more pronounced in women than in men. Its lack of/inverse association with nitrite and blood pressure confirms T ₅₀ to be orthogonal to traditional cardiovascular disease risk factors. Lower T ₅₀ was associated with a more favorable serum lipid profile, suggesting the involvement of divergent pathways of calcification stress and lipid stress in the pathophysiology of myocardial infarction.

Galectin-3 and Suppression of tumorigenicity-2 (ST2) are known markers of cardiac fibrosis. We investigated the prognostic value of fibrotic markers for the development of diastolic dysfunction and long-term outcome in patients suffering an ST-elevated myocardial infarction (STEMI). We analyzed 236 patients from the GIPS-III cohort with available echocardiographic studies and plasma measurements at hospitalization and after 4 months follow-up. Adjusted logistic mixed effects modelling revealed no association between the occurrence of diastolic dysfunction over time with abnormal plasma levels of galectin-3 and ST2. We observed no differences regarding survival outcome at follow-up of 5 years between patients with normal versus abnormal values in both galectin-3 (P = 0.75), and ST2 (P = 0.85). In conclusion, galectin-3 and sST2 were not associated with the development of diastolic dysfunction in non-diabetic patients that presented with a STEMI.

Background: Adverse systolic remodeling after ST-elevation myocardial infarction (STEMI) is associated with poor clinical outcomes. However, little is known about diastolic remodeling. The purpose of this study was to identify the factors leading to diastolic remodeling. Methods: Echocardiography was performed during hospitalization and at 4 months follow-up in 267 non-diabetic STEMI patients from the GIPS-III trial. As parameters of diastolic remodeling we used (1.) the E/e′ at 4 months adjusted for the E/e′ at hospitalization and (2.) the change in E/e′ between hospitalization and 4 months. Multivariable regression models correcting for age and sex were constructed to identify possible association of clinical and angiographic variables as well as biomarkers with diastolic remodeling. Results: Older age, female gender, hypertension, multi vessel disease, higher glucose and higher peak CK were independent predictors of higher E/e′ at 4 months in a multivariable model (R²:0.20). After adjustment for E/e′ during hospitalization only female gender, multivessel disease and higher glucose remained predictors of E/e′ at four months (R²:0.40). Lower myocardial blush grade, AST and NT-proBNP were independent predictors of a higher increase of E/e′ between hospitalization and at 4 months in a multivariable model (R²:0.08). Conclusions: Our data supports the hypothesis that female gender, multivessel coronary artery disease, and microvascular damage are important predictors of adverse diastolic remodeling after STEMI. In addition, our data suggests that older age and hypertension prior to STEMI may have contributed to worse pre-existing diastolic function. Trial registration: NIH, NCT01217307. Prospectively registered on October 8th 2010, https://clinicaltrials.gov/ct2/show/NCT01217307.